Essential involvement of CX3CR1-mediated signals in the bactericidal host defense during septic peritonitis
Essential involvement of CX3CR1-mediated signals in the bactericidal host defense during septic peritonitis
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DOI：
10.4049/jimmunol.181.6.4208
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发表时间：
2008-09-15
影响因子：
4.4
通讯作者：
Kondo, Toshikazu
中科院分区：
文献类型：
--
作者：
Ishida, Yuko;Hayashi, Takahito;Kondo, Toshikazu
盲肠结扎和穿孔（CLP）导致野生型（WT）小鼠的脓毒性腹膜炎，术后7天内死亡率接近33%。同时，腹膜内CX 3CL 1/fractalkine的蛋白水平增加，CX 3CR 1表达的巨噬细胞浸润到腹膜中。CLP在CX 3CR 1缺陷（CX 3CR 1（-/-））小鼠中诱导75%的死亡率，然而，其表现出与WT小鼠相似程度的腹膜内白细胞浸润。尽管如此，与WT小鼠相比，CX 3CR 1（-/-）小鼠表现出腹膜内细菌清除受损，以及腹膜内诱导型NO合酶（iNOS）和杀菌促炎细胞因子（包括IL-1 β、TNF-α、IFN-γ和IL-12）表达减少。与WT小鼠相比，CX 3CR 1（-/-）小鼠中腹膜吞噬细胞（如中性粒细胞和巨噬细胞）的杀菌能力持续减弱。此外，当WT巨噬细胞在体外刺激CX 3CL 1，其杀菌活性增强剂量依赖性的方式，增强iNOS基因表达和随后的NO生成。此外，CX 3 CL 1增强了具有NF-κ B活化的WT巨噬细胞的IL-1 β、TNF-α、IFN-γ和IL-12的基因表达。因此，CX 3 CL 1-CX 3 CR 1相互作用通过激活吞噬细胞的细菌杀伤功能，并通过主要通过NF-κ B信号途径增加iNOS介导的NO产生和杀菌促炎细胞因子产生，对巨噬细胞浸润几乎没有影响，对于针对细菌感染的最佳宿主防御至关重要。
Cecal ligation and puncture (CLP) caused septic peritonitis in wild-type (WT) mice, with similar to 33% mortality within 7 days after the procedure. Concomitantly, the protein level of intraperitoneal CX3CL1/fractalkine was increased, with infiltration by CX3CR1-expressing macrophages into the peritoneum. CLP induced 75% mortality in CX3CR1-deficient (CX3CR1(-/-)) mice, which, however, exhibited a similar degree of intraperitoneal leukocyte infiltration as WT mice. Despite this, CX3CR1(-/-) mice exhibited impairment in intraperitoneal bacterial clearance, together with a reduction in the expression of intraperitoneal inducible NO synthase (iNOS) and bactericidal proinflammatory cytokines, including IL-1 beta, TNF-alpha, IFN-gamma, and IL-12, compared with WT mice. Bactericidal ability of peritoneal phagocytes such as neutrophils and macrophages was consistently attenuated in CX3CR1(-/-) mice compared with WT mice. Moreover, when WT macrophages were stimulated in vitro with CX3CL1, their bactericidal activity was augmented in a dose-dependent manner, with enhanced iNOS gene expression and subsequent NO generation. Furthermore, CX3CL1 enhanced the gene expression of IL-1 beta, TNF-alpha, IFN-gamma, and IL-12 by WT macrophages with NF-kappa B activation. Thus, CX3CL1-CX3CR1 interaction is crucial for optimal host defense against bacterial infection by activating bacterial killing functions of phagocytes, and by augmenting iNOS-mediated NO generation and bactericidal proinflammatory cytokine production mainly through the NF-kappa B signal pathway, with few effects on macrophage infiltration.